Estrogen receptor (ER) and overexpressed Her2 are two major oncogenic proteins in hormone positive breast cancers. Current treatments to block ER or Her2 have been shown to effectively slow tumor growth. However, the need to overcome arising drug resistance has led to the development of combination and adjuvant drugs as new therapeutic approaches.
Phosphatidylinositide 3-kinases (PI 3-kinases, PI3Ks, PI(3)Ks, PI-3Ks, phosphatidylinositol-3-kinases, or phosphoinositide 3-kinases) are a family of enzymes involved in cellular functions, such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. PI3Ks are a family of related intracellular signal transducer enzymes capable of phosphorylating the 3 position hydroxyl group of the inositol ring of phosphatidylinositol.
Histone deacetylase (HDAC) inhibition can cause breast cancer cell growth arrest, and has been reported to repress both ER and Her2 transcription. However, Class I HDAC inhibition leads to significant adverse effects and an alternative HDAC inhibition profile is desirable, particularly in combination with other therapeutic agents.
HDAC6 is a Class IIb HDAC and is known to remove acetyl groups from many cellular proteins, including α-tubulin and HSP90. It has been reported that HSP90 hyperacetylation destabilizes its target proteins, including ER and EGFR. Inhibitors of HDAC6 have demonstrated anti-cancer proliferative activity in various cancer types, including Her2+ breast cancer. Blocking HDAC6 activity has been shown to cause Her2+ breast cancer cell growth inhibition through various mechanisms, including destabilization of Her2 mRNA and protein.
Due to the dose-limiting toxicities of the non-selective HDAC inhibitors, there is an ongoing need in the art for more efficacious and less toxic compositions and methods for the treatment of breast cancer. In order to meet these needs, provided herein are pharmaceutical combinations comprising an HDAC inhibitor and either a Her2 inhibitor or a PI3K inhibitor, and methods for the treatment of breast cancer. The combinations and methods of the invention are well tolerated and do not exhibit the dose-limiting toxicities of prior therapies.